We recently discovered that various Parkinson-related proteins, including parkin, DJ-1, and protein-disulfide isomerase (PDI), are S-nitrosylated and then further oxidized (published in PNAS, Science, and Nature). S-Nitrosylation (chemical transfer of an NO group to a critical cysteine thiol) affects protein function - in the case of parkin, regulating its E3 ligase activity;for PDI contributing to protein misfolding;and for DJ-1, possibly affecting DJ-1 dimerization or its interactions with PINK1 and thus the stability of the parkin/PINK1/DJ-1 complex (as shown by Dr. Z. Zhang in Project 1 of this NIEHS Center Grant Application). These S-nitrosylation reactions appear to contribute to the pathogenesis of Parkinson's disease. Here, we will further study these nitrosylation reactions with the Proteomics Core (Core B), seek structural evidence for their basis with the Structural Core (Core C), and perform high-throughput screening with our Chemical Library Core (Core E) to develop novel drugs that prevent these nitrosylation reactions and that are therefore potentially neuroprotective. These drugs will be tested subsequently within this project in secondary screens for neuronal survival on primary neurons in vitro here in Project 3, and in mouse transgenic (tg) models of PD in conjunction with the Neuropathology and Animal Behavior Core (Core D).